JP2019026648A - 血液脳関門を通過して輸送するための組成物及び方法 - Google Patents
血液脳関門を通過して輸送するための組成物及び方法 Download PDFInfo
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Abstract
Description
本出願は、その全内容が参照により本明細書に援用される、2011年6月3日に出願された米国仮出願第61/492,884号優先権を主張し、その利益を主張する。
本発明は、国立衛生研究所によって与えられた5R43MH094004−01及び5R43MH094004−02の下での政府支援を受けてなされた。政府は、本発明において一定の権利を有する。
本開示は、血液脳関門を横切ることができる組成物、及び血液脳関門内の標的にエフェクター剤を送達させるためのこれらの組成物を使用する方法に関する。
ヒトlynx1−ループ2ドメインとマウス、マカク、ウシ、チンパンジー、リスザル、ラット及びフェレット由来のlynx1−ループ2配列のアラインメントを図9に示す。本発明のいくつかの実施形態において、例えば、本明細書に開示されているエフェクター剤にコンジュゲートされたlynx1−ループ2由来のペプチド輸送因子を注射した対象の脳切片の細胞画像又は共焦点顕微鏡によって決定されるように、lynx1−ループ2に由来するペプチドは、細胞取込み及び/又はBBBを横切る輸送を付与する。したがって、本発明のいくつかの実施形態において、lynx1−ループ2由来ペプチドは、一般配列X1−X2−X3−X4−X5−X6−X7−X8−X9−X10−X11−XI2−X13−X14−X15−X16(配列番号1)を有する16マーのペプチドであり、ここで、配列番号1については以下の通りである。
X2は、T又はIであり;
X3は、T又はWであり;
X4は、R又はCであり;
X5は、T又はDであり;
X6は、Y、I、又はGであり;
X7は、F又はYであり;
X8は、T又はCであり;
X9は、P、N、又はSであり;
X10は、Y、T、又はSであり;
X12は、M又はGであり;
X14は、V又はRであり;
X15は、R、S、A、又はIであり;
X16は、K、S、又はDである。
X4は、R又はCであり;
X5は、T又はDであり;
X6は、任意のアミノ酸であり;
X7は、F又はYであり;
X8は、任意のアミノ酸であり;
X9は、任意のアミノ酸であり;
X10は、任意のアミノ酸であり;
X12は、M又はGであり;及び
X14は、V又はRである。
X4は、R又はCであり;
X5は、T又はDであり;
X6は、Y、G、又はIであり;
X7は、F又はYであり;
X8は、T又はCであり;
X9は、P、N、又はSであり;
X10は、Y、T、又はSであり;
X12は、M又はGであり;及び
X14は、Vである。
X4は、R又はCであり;
X5は、T又はDであり;
X6は、Y、G又はIであり;
X7は、F又はYであり;
X8は、Tであり;
X9は、Pであり;
X10は、Y又はTであり;
X12は、M又はGであり;及び
X14は、Vである。
本発明のlynx1由来ペプチドは、血液脳関門を通過することができ、また、それが標的細胞及び/又は分子への送達のためにコンジュゲートされるエフェクター剤をターゲティングすることができる。エフェクター剤が本発明のlynx1由来ペプチドとコンジュゲートし、連結され又は複合化され得るエフェクター剤及び方法の例には、本明細書、及び全ての全内容が参照により本明細書に援用されるKumarら,Nature 448:39−43,2007;Pulfordら,PLoS One 5:e11085,2010;Rohnら,J Drug Target,20:381−388,2012に開示されるsiRNA;全内容が参照により本明細書に援用されるHwang doら,Biomaterials,32:4968−4975,2011に記載されるhsRNA又はマイクロRNA;全内容が参照により本明細書に援用されるPardridge, Jpn J.Pharmacol,87:97−103,2001に記載されるオリゴヌクレオチド(DNA又はRNA);Pardridge,2011(上述)に記載される修飾されたオリゴヌクレオチド(例えば、DNA又はRNA);Pardridge,2011(上述)、及び全内容が参照により本明細書に援用されるGongら,Biomaterials,33:3456−3463,2012に記載される遺伝子;Pardridge,2011(上述)に記載されるペプチド及びPETリガンド;Pardridge,2011(上述)、及び全内容が参照により本明細書に援用されるXiangら,J Drug Target,19:632−636,2011に記載されるタンパク質;全内容が参照により本明細書に援用されるZhanら,Mol Pharm,7:1940−1947,2010に記載される小化学分子;大化学分子;ウイルス粒子;Pulfordら,2010(上述)に記載されるリポソーム;エンドソーム;全内容が参照により本明細書に援用されるAlvarezら,Nat.Biotechnol,29:341−345,2011に記載されるエキソソーム;全内容が参照により本明細書に援用されるChenら,J Drug Target,19:228−234,2011及びLiuら,Biomaterials,30:4195−4202,2009に記載されるナノ粒子;Lirら(上述)に記載されるデンドリマー(例えば、PAMAM);真核細胞;原核細胞;全内容が参照により本明細書に援用されるPatelら,CNS Drugs,23:35−58,2009に記載されるマイクロスフェア、ナノゲル及びバイオナノカプセルが挙げられる。
本発明のいくつかの実施形態において、血液脳関門を通過させて脳内の標的にペプチドを輸送する方法は、標的を含む対象又は細胞培養物にlynx1−ループ2由来ペプチドを提供することを含む。いくつかの実施形態において、BBB内で見出された標的に到達することができるlynx1−ループ2由来のペプチドは配列番号1を有する。他の実施形態において、ペプチドは、配列番号2、3、4又は5の配列を有する。さらに他の実施形態においては、ペプチドは、配列番号1の配列を有し、配列番号8のペプチドは残基3と4の間に挿入される。
本発明のいくつかの実施形態において、標的細胞にエフェクター剤を輸送させる方法は、複合体を形成するために、エフェクター剤にlynx1−ループ2由来のペプチドをコンジュゲートさせ、標的細胞又は標的細胞を有する対象に複合体を提供することを含む。
1モル比:
Claims (15)
- 配列番号10の配列を含む輸送因子ペプチドを含む組成物。
- エフェクター剤をさらに含む、請求項1に記載の組成物。
- エフェクター剤が、siRNA、shRNA、マイクロRNA、二本鎖RNA、鎖鋳型RNA、オリゴヌクレオチド、修飾オリゴヌクレオチド、アプタマー、並びにオリゴヌクレオチド、遺伝子、ペプチド、タンパク質、低化学分子、大化学分子、ウイルス粒子、リポソーム、エンドソーム、エキソソーム、ナノ粒子、デンドリマー、陽電子放出断層撮影(PET)リガンド、真核細胞、原核細胞、マイクロスフェア、ナノゲル及びバイオナノカプセルの組み合わせからなる群から選択される、請求項2に記載の組成物。
- エフェクター剤がsiRNAである、請求項2に記載の組成物。
- 配列番号10の配列を含む輸送因子ペプチドと、該輸送因子ペプチドにコンジュゲートされたエフェクター剤を含む輸送因子ペプチドコンジュゲートを含む組成物。
- 血液脳関門を横切って見出される標的に配列番号10の配列を含む輸送因子ペプチドを輸送するための医薬組成物であって:
インビボ又はインビトロにある標的に前記輸送因子ペプチドを輸送するのに適した、上記医薬組成物。 - 血液脳関門を横切って見出される標的に、配列番号10の配列を含む輸送因子ペプチドと、該輸送因子ペプチドにコンジュゲートされたエフェクター剤を含む輸送因子ペプチドコンジュゲートを輸送するための医薬組成物であって:
血液脳関門の受容体に輸送因子ペプチドコンジュゲートを輸送するのに適した、上記医薬組成物。 - 標的に輸送因子ペプチドコンジュゲートを輸送することが、インビトロの細胞培養において行われる、請求項7に記載の医薬組成物。
- 標的に輸送因子ペプチドコンジュゲートを輸送することが、マウス又はヒトの対象において行われる、請求項7に記載の医薬組成物。
- 血液脳関門の受容体が細胞又は細胞外分子上にある、請求項7に記載の医薬組成物。
- 細胞が、ニューロン、神経細胞、脳細胞、グリア細胞、星状細胞、神経支持細胞、及び中枢神経系の細胞からなる群から選択される、請求項10に記載の医薬組成物。
- 血液脳関門の受容体がニコチン性受容体である、請求項10に記載の医薬組成物。
- 細胞外分子がタンパク質を含む、請求項10に記載の医薬組成物。
- エフェクター剤が、siRNA、shRNA、マイクロRNA、二本鎖RNA、鎖鋳型RNA、オリゴヌクレオチド、修飾オリゴヌクレオチド、アプタマー、並びにオリゴヌクレオチド、遺伝子、ペプチド、タンパク質、低化学分子、大化学分子、ウイルス粒子、リポソーム、エンドソーム、エキソソーム、ナノ粒子、デンドリマー、陽電子放出断層撮影(PET)リガンド、真核細胞、原核細胞、マイクロスフェア、ナノゲル及びバイオナノカプセルの組み合わせからなる群から選択される、請求項7に記載の医薬組成物。
- エフェクター剤がsiRNAである、請求項7に記載の医薬組成物。
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